In this analysis of combined observational data from 2 European studies involving 7573 mother–child pairs exposed to HAART in pregnancy, we found no evidence of a difference in risk of detectable maternal viral load at delivery, MTCT, or congenital abnormality when comparing ZDV-sparing with ZDV-containing HAART. Overall, 16% of women were prescribed ZDV-sparing HAART during pregnancy in this population. The fact that most women initiated ZDV-containing HAART during pregnancy even in 2009 was not surprising in light of the evidence base for use of ZDV in pregnancy; however, we saw an increase in initiation of ZDV-sparing HAART during pregnancy between 2000 and 2009. In general, use of ZDV-sparing HAART increased over time between 2000 and 2009, particularly among women conceiving on HAART, with approximately 1 in 3 HIV-infected pregnant women receiving ZDV-sparing HAART in 2009.
About 27% of women had a detectable viral load at delivery, similar to rates reported elsewhere,7,28
and there was no difference whether ZDV was used. The estimated overall rate of MTCT was 0.9%, consistent with other European data,7
and we found no association with ZDV-sparing HAART. We found no increased risk of congenital abnormality with use of ZDV-sparing HAART. This finding is in line with data from the Antiretroviral Pregnancy Registry, which has not detected an increased risk of congenital abnormality among infants exposed to stavudine, ABC, or TDF.14
The rate of congenital abnormality reported here was similar to that previously reported in the NSHPC.21
This is the first large-scale analysis of observational data sets looking specifically at adverse maternal and infant outcomes after use of ZDV-sparing HAART in pregnancy. Comparison with other sources of population surveillance data for HIV29
suggests that virtually all diagnosed HIV-infected women in the United Kingdom and Ireland are reported to the NSHPC through its complementary reporting systems.30
Nonenrolment in the ECS is approximately 5% and is due to migration rather than refusal, with no systematic exclusion.31
Although there was a substantial amount of missing data (46%) for delivery viral load, these data were more frequently missing for women on long-term treatment; because virologically suppressed women on long-term treatment probably had less frequent monitoring, and hence less chance of having viral load measured close to delivery, we are likely to have overestimated the proportion of women with detectable viral load at delivery. This is supported by the decreased risk of MTCT in women with missing delivery viral load although this difference was not statistically significant. Given that there was no difference in the proportion of missing data in the ZDV-sparing and ZDV-containing groups, missing data would have resulted in reduced precision but not necessarily biased estimates. In a fifth of cases, infant HIV status had not yet been reported. This was strongly associated with delivery in later years, between 2007 and 2009, and is mainly a result of delay in reporting final laboratory results. Previous sensitivity analyses have shown that this is likely to have a minimal effect on MTCT estimates for the United Kingdom and Irish data.5
In this analysis, ZDV-containing HAART was defined as any ZDV exposure in pregnancy and included regimen switches to or from a ZDV-sparing regimen during pregnancy. More detailed information on regimen switches and discontinuation during pregnancy was not available for this analysis. There were no data on other potential confounders such as adherence to antiretroviral therapy, socioeconomic status, smoking, and alcohol use in pregnancy. Data on pregnancy complications and maternal coinfections have only recently been routinely collected in the studies and were not available for this analysis.
We were unable to conduct drug-specific analysis with regard to ZDV-sparing regimens due to small numbers. With increasing use of both TDF and ABC and consequently improved power to detect differences in outcomes, drug-specific analysis is a priority in the future. In this analysis, we were unable to explore long-term consequences of in utero exposure to ZDV-sparing HAART. This is of importance given recent data on TDF and long-term renal and bone toxicity in adults, children, and animal models.19,20,32,33
Data on children reported to the NSHPC are linked to routinely collected cancer and death registrations in England, but information on other health outcomes is not currently available.34,35
Although long-term follow-up of uninfected children exposed to ZDV-sparing HAART in utero would be desirable, it is a challenging undertaking.36
Given the possible adverse effects of in utero exposure to ZDV37–39
and concerns regarding other drugs, continued pharmacovigilance of all antiretroviral drugs in pregnancy should remain a priority. As clinical trials in pregnancy are not feasible, observational data are needed to provide evidence of the equivalence of newer antiretroviral agents that are not currently licensed for use in pregnancy.
In conclusion, this large-scale analysis of European observational data including more than 7500 mother–child pairs showed that overall outcomes for women on ZDV-sparing HAART in pregnancy are similar to those in women on ZDV-containing regimens. This is reassuring given that a third of women delivering in these studies are now receiving ZDV-sparing HAART in pregnancy, with the trend towards increasing use likely to continue.